Taxanes include paclitaxel (trade name: Taxol) and docetaxel (trade name: Taxotem), two types of anti-cancer drugs of taxanes approved by Food & Drug Administration (FDA). They both belong to water-insoluble drugs, which can hardly be dissolved in water (about 4 μg/ml of water-solubility) and only 2%-4% is absorbed after oral administration. Hence, they can only be administrated intravenously. In order to enhance the water-solubility of paclitaxel, available paclitaxel injection is a colorless viscous concentrated solution prepared by a mixed solvent of polyoxyethylene castor oil and anhydrous ethanol in the ratio of 50:50 (v/v). Although the presence of composite solvent enhances the solubility of paclitaxel, a series of side effects are easily induced by the solubilizer, particularly polyoxyethylene castor oil, which is contained in this injection. The side effects of the available paclitaxel preparations after administration are severe: dyspnea, flushing face, palpitation and allergic reaction such as skin rash etc, which brings a lot of potential safety troubles and suffering to the patients. Similarly, there are problems in available docetaxel preparation. The clinical preparation of docetaxel is composed of Tween-80 solution and 13% ethanol solution. Although the addition of normal saline when administrating it to the patients through intravenous drip ameliorates solubility of docetaxel, yet Tween-80, utilized as a solubilizer in this injection, has an effect for hemolysis to some degree. Therefore, the available docetaxel preparation has less drug safety in the clinical application. Considering many drawbacks in available clinical applications, the research works on taxane drugs injection preparations become more and more active.
Fortner et al. (Am. J. Hosp. Pharm. (1975) 32, 582-584)) has reported a new dosage form for water-insoluble drug by dissolving them in a suitable solvent for injection to prepare a pharmaceutical solution, which was followed by adding with emulsion for injection when administrating it to the patients through intravenous drip. This dosage form has been taken more seriously ever since.
In the application entitled “Parenteral paclitaxel in a stable non-toxic formulation” filed by B. S Anderson (Chinese pat. No.: 97196934.5), the solvent of pharmaceutical solution was composed of PEG-400 and dimethylacetamide in the ratio of 3:1, in which the dimethylacetamide, utilized as a solubilizer by helping to enhance drug solubility though, increased effects of the preparation for inducing toxicity and side effect. Therefore, dimethylacetamide utilized as a solubilizer may increase toxicity and side effect for the preparations. Zhou Lianfang et al. (Research progress on the toxicity of dimethylacetamide [J]. China Occupational Medicine, (2009), 36 (1): 66-67) pointed out that dimethylacetamide could cause multiple severe injuries on mice and rats, such as weight loss, atrophy of the retina, change of brain electric wave, as well as a lot of injuries to organs of lung, stomach, liver and kidney etc.
In the application entitled “Pharmaceutical composition containing hardly water soluble medicament” filed by Takeda Koichi et al. (Chinese Appl. No.:200680007345.3), the solvent of pharmaceutical solution was mainly composed of PEG-400 and oleic acid. As indicated by R. C. Roche (Handbook of Pharmaceutical Excipients, original 4th edition: 476), the oleic acid might lead to hemocytocatheresis, namely effect of hemolysis. It is permitted only in non-injected preparations in Britain.
In the application entitled “A concentrated emulsion containing taxane compound and its using method” filed by Hu Yufang (Chinese Appl. No.:200410025522.3), the pharmaceutical solution was prepared into a mixed solvent containing surfactant, such as Tween-80, PVP and lecithin etc. These surfactants have both hemolytic activity and irritation.
Now, the key technology on which is focused mainly is the properties of selected material such as biocompatibility, in vivo tolerance and stability of dosage form. In despite of breakthrough that has been made in researches on some dosage forms, the clinical application is still restricted on account of low drug loading and short stabilization time, therefore making it impossible to reach an effectively therapeutic concentration. In the application developed by the present inventors and entitled “A taxane intravenous infusion preparation and its preparative method” (Chinese Appl. No.: 200810100234.8), no toxic solubilizer was contained, for example polyoxyethylene castor oil, Tween-80, dimethylacetamide, oleic acid and PVP etc, which finally makes its safety and stability improved significantly.
The present invention is a further research based on the Chinese patent application (Pat. Appl. No.: 200810100234.8). It was found that dispersion of emulsion in pharmaceutical solution, within a specific range of pH value, would make stabilization time and appearance better than that could be expected. The stabilization time was prolonged markedly; there was no floating oil on the surface of dispersed solution and the appearance was desirable. Clinically, safety and effectiveness of drugs were further improved. Consequently, the present invention belongs to an improved intravenous infusion preparation of taxanes and preparation method thereof.